Adipose Tissue & Body Fat: Obesity, Insulin, Leptin, Fertility, Weight Loss & GLP-1 Drugs | Sean Hartig | #174

About the guest: Sean Hartig, PhD is an associate professor at the Baylor College of Medicine, where is lab studies adipose (fat) tissue, metabolic regulation, and obesity & energy balance disorders.

Episode summary: Nick and Dr. Hartig discuss: visceral vs. subcutaneous fat; white, brown, and beige adipose tissue; physiology of fat cells; obesity, insulin resistance, and leptin resistance; hormones & fertility; GLP-1 drugs for weight loss; and more.

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Sean Hartig 3:44

I'm an associate professor of medicine and cell biology at Baylor College of Medicine in Houston, Texas. I've been at Baylor since 2008 and I have a non conventional, uh ascension through the system, in contrast to a lot of people we recruit from the outside, I survived an inside track to where I am today. So I was a postdoc, post doctoral fellow here, and then was promoted to an entry level faculty position, and I was fortunate enough to secure funding independently, and that allowed me to establish my research laboratory in my laboratory since about 2009 when I was a postdoctoral fellow, has been focused on the cell biology of of fat cells, and we've been interested in understanding, number one, how fat cells respond to external. Signals, and how they turn those external signals into mechanisms that are important for storing energy and disposing of energy, and this is really important for physiology and mammals, because adipose tissue is the reservoir for storing energy when we need it, not just during times when food's not available, but also to liberate energy during infection in adipose tissue and fat cells. It gets sort of a bad reputation because it's mostly associated with obesity and being overweight. However, adipose tissue is this really cool endocrine organ too. It's not just important for storing energy, it's also really fundamentally vital for regulating glucose metabolism. People that lack adipose tissue have conditions called lipodystrophies, and they develop similar syndromes as people with type two diabetes, really,

Nick Jikomes 6:09

yes. So, so people basically might have, say, a genetic condition where they completely lack fat tissue or fat cells, and they basically have a disrupted endocrine system,

Sean Hartig 6:21

yes, so they develop these individuals have insulin resistance and diabetes conditions that are oftentimes worse than people who have obesity and type two Diabetes. And in fact, there's been a number of studies from prominent journals like cell metabolism that demonstrated people that have led with dystrophies and are of low BMI, low body mass index, they're at a greater risk of conditions like liver cancer than people who are obese. So the this concept that adipose tissue is important for regulating metabolism in the whole body is really founded in important principles that were that are related to how much adipose tissue that you accumulate in the body and where it's stored. And so my lab is interested in understanding what are the properties of fat cells that produce those metabolic benefits in animal models and in people.

Nick Jikomes 7:35

So obviously, when people think about healthy levels of fat on the body, we tend to think about, you know, not having too much. And you know, you can understand why. It's pretty obvious why, where we have an obesity epidemic, but it sounds like, if you go in the other direction, if your body fat's too low, that's that's also problematic. And as you mentioned, those conditions where people don't have any body fat, but they still have type two develop Type Two Diabetes and insulin resistance. I guess that also is one way to show us that even though obesity and diabetes often go hand in hand, they are, in fact, dissociable.

Sean Hartig 8:11

They are. They are. There's a fairly sizable population of people in this country in who have obesity yet have normal measures of insulin sensitivity and glucose levels and serum lipids, and those people have a predisposition or a propensity for storing fat and subcutaneous depots so placebotics and in the thighs. It's unclear right now whether these types of metabolically healthier forms of obesity are are a transient state, but there is a large population of people where this appears to be a long term adaptation, or perhaps buried in genetics, somehow.

Nick Jikomes 9:06

And so subcutaneous fat, that would be in contrast to visceral fat. Can you explain the difference there? For people, subcutaneous

Sean Hartig 9:12

fat is the adipose tissue that's underneath the skin, and it's actually the largest depot for adipose tissue, so 80% of your fat cells are located in subcutaneous depots. Visceral fat is the adipose tissue that's accumulating in in the intra abdominal space, and it's thought that when subcutaneous fat reaches its maximal storage potential, that's when you start to see spillover of energy that's stored in abdominal fat tissue. And. Uh, abdominal fat is really the adipose tissue depot that's predictive of cardiometabolic disease and insulin resistance. It's also associated with fatty liver disease and insulin resistance. And one interesting is that in a number of animal studies, these two depots arise from completely different cellular lineages. The lineage for subcutaneous fat is coming from the mesoderm, whereas visceral fat comes from from from a completely different origin that's related to, sort of nearer to the mesothelial cell of origin.

Nick Jikomes 10:55

So these aren't just when we say visceral versus subcutaneous fat, it's not merely a description of different locations where fat can go. Anatomically speaking, these are completely different cells that belong to different lineages of the body.

Sean Hartig 11:09

Yes, they are, for lack of a better description, there are different organs and they behave differently. They all respond to anabolic hormones like insulin, but their behavior is quite different. And that's really a fundamental question that we would like to understand in our lab, is what makes them different, what makes them the same? And when does adipose tissue ultimately become bad, and that's really at the heart of all the questions that we want to try to understand in my lab,

Nick Jikomes 11:48

and when we think about so you said, when does adipose tissue become bad? I think that the naive way people think about fat is that it's bad when you have too much of it, which implies that if you just keep stacking, you know, more and more fat cells on top of each other, or filling them up with more fat. You know, at some point we just draw a line in the sand and we say, That's too much. But I'm wondering if there's more to it than that does. Does the actual like physiology, the actual functional stuff that the fat cells are doing. Does that change in in a state of obesity, or in a state of diabetes or in a different metabolic state? Does it actually change like inside the person at some point and start you know these fat cells are doing different things?

Sean Hartig 12:33

Yes, there's a there's a wide breadth of knowledge that that suggests that that's precisely true, that in states of excess energy, that adipose tissue changes its and loses its ability to store glucose derived carbon as lipid efficiently. There's also, you know, a lot of really nice evidence that suggests that the size of the fat cell is really predictive of, you know, metabolic declines in function. So if your subcutaneous fat has more smaller adipocytes, that actually provides greater surface area for storing energy more efficiently, as in abdominal fat depots, where you have larger fat cells, those are generally associated with glucose intolerance and insulin resistance. And those larger fat cells, despite being bigger, actually store energy less efficiently. And so those are really, you know, important differences between how adipose tissue responds and ultimately, how it predicts metabolic consequences of obesity.

Nick Jikomes 13:55

In in a lean, metabolically healthy person, what are the different types of fat cells? So we talked about subcutaneous versus visceral, and that those are different. They're not just anatomical differences being referred to there. But what about like, white and brown fat? Are there different like, very different types or distinct types of fat cells that have very different physiological functions? Yeah.

Sean Hartig 14:19

So this is a very pointed matter in the field, and there are different shades of adipose tissue. And right now, there's a belief that at least three exists, and those three are white, fat, brown fat, and then what's called beige fat. And white fat is the type of adipose tissue that has the greatest familiarity. It's mostly implicated with the consequences of obesity and. A brown fat is an adipose tissue depot that is important for generating heat in rodents. It performs thermogenesis, which is the process of generating heat in response to cold, cold and thermogenic stimuli. Beige fat is a newer form of adipose tissue that was identified, and this is a this is a type of adipose tissue that is not purely brown fat and not purely white fat, but expresses many features of both. And it's not that this type of fat is pretty abundantly present in people and important for regulating insulin sensitivity widely. So Diabetes drugs like thiazolidinediones tend to activate beige fat very strongly, and that's important for producing metabolic benefits in people. Brown fat is more hotly debated topic. There's really no doubt that brown adipose tissue is present in rodents, and because it's vitally important for regulating rodent body temperature. However, in humans, there is evidence that it's present. However, its function is pretty well debated in the field. There's pretty great evidence in a lot of good journals that the amount of human brown fat declines with age. However, it's not quite clear that the thermogenic functions of brown adipose issuing people that being the generation of heat, is substantive enough to burn calories and cause weight loss. And this is a fairly new concept, because it was thought that brown adipose tissue in humans was lost after was is present in babies, right? It's present back of babies in part of the mechanism to keep babies warm, but that was steadily lost as you grow up. And then there was a really pioneering story from a couple of groups that identified FDG, pet positive brown fat in the shoulder, intercalvicular regions of humans. And this was really an exciting time, because if you could turn on those adipose tissue depots and cause them to burn calories selectively, that would be that would be wonderful for causing weight loss. And it turns out, there hasn't been a lot of success in developing therapies or interventions that activate human brown fat enough to burn calories and cause weight loss, but there are a number of interesting studies that have suggested that brown fat in people's, in people and in rodents, can have endocrine effects that are important for systemic physiology

Nick Jikomes 18:28

I see so if I'm hearing you correctly, so far on the brown fat, brown fat exists. It probably exists in most or all mammals. It definitely exists and definitely causes thermogenesis in rodents, and it is probably less prominent and less physiologically potent, at least in that respect. In humans, it's not clear whether or not the brown fan is doing the same thing in humans as it does in rodents. Maybe it's doing other things it doesn't do in rodents. Maybe it's sort of like a bit of an evolutionary remnant. Is, is that sort of maybe a possibility here.

Sean Hartig 19:01

I mean, I guess that's possible, that it's an evolutionary remnant,

Nick Jikomes 19:06

but it's still quite mysterious in terms of human function, yes, in adult humans, okay, so in babies, though, it is sort of a bona fide thermogenic tissue,

Sean Hartig 19:17

yes, yes, yes. And you know, the holy grail would be, especially shortly after this depot was rediscovered in adults, would be, if you could activate brown fat selectively turn on the thermogenic function in some way that was, that was positive, you could burn calories right? Other than uh, burn calories through the activation of mitochondria in in brown fat.

Nick Jikomes 19:48

So, so when you say burn calories, it's it sounds like activating, uh, brown adipose tissue would likely result, based on our knowledge, in in the burning of fat. Elsewhere in the body. And if that's the case, I'm wondering how that happens, how that communication across tissues would happen?

Sean Hartig 20:09

So sorry say that again.

Nick Jikomes 20:12

So the brown adipose tissue thermogenesis phenomenon in rodents or another species, say when that happens, is, are you simply burning away the brown adipose tissue, or do you burn away fat elsewhere in the body? Oh,

Sean Hartig 20:27

so brown adipose tissue is a really great place for burning carbohydrates and lipids. So it's a sink for consuming these things. And instead of generating ATP, what brown fat does is it generates chemical energy as heat, and it performs its function by dissipating the chemical energy gradient in the mitochondria and affecting hydrogen ion exchange across the mitochondrial gradient. It also is important for burning some amino acids as well, so it can perform sink like functions for burning both sugars and fat. And it's not that it gets bigger per se or gets smaller. It performs its function and sort of sustains its volume. There are no known ways that I'm aware of and people that can make more brown fat, I

Nick Jikomes 21:43

see, so it's a pretty stable organ, and in a sense,

Sean Hartig 21:47

yes it Yes, but for reasons that are not totally clear in aging, the presence of FDG positive brown fat begins to decline.

Nick Jikomes 22:01

And what like in a normal, like, healthy person, what percentage of the fat would be Brown versus white? Say,

Sean Hartig 22:07

oh, I don't know the top of my head. I mean, we're talking about perhaps magnitude differences.

Nick Jikomes 22:17

So yeah, we, I would guess that we have much more white adipose tissue. Yes,

Sean Hartig 22:22

I mean, I hesitate to say what the actual number is. I don't know off the top of my head that being said, not knowing that number means the the amount of white fat is far, far greater than the amount of brown fat in people. Um, rodents have a quite, a quite a large amount of brown fat that's located in their interscapular space. Presumably,

Nick Jikomes 22:52

that's because they're so small, they're much more prone to hypothermia.

Sean Hartig 22:57

Their size definitely is part of the reason they need brown fat to to burn energy.

Nick Jikomes 23:06

So when we think about fat and energy storage in the endocrine functions of fat cells, and you know what they do beyond just being a storage receptacle for energy for us to burn later, what like Can you can you describe for people a little bit, maybe paint us a picture at the cellular level of how fat is stored. And we'll start there is, you know, is the whole is a fat cell, literally just ballooning up with fatty acid molecules. What does the storage look like on a cellular level?

Sean Hartig 23:38

So the fat cell is, a cell that's uniquely responsive to anabolic hormones like insulin and when glucose levels get high after a meal and achieve first pass circulation, through the intestine and out past the liver, insulin axon, adipose tissue to clear glucose from circulation, and adipose tissue is really specialized to take that glucose and perform glycolysis and the TCA cycle to generate the intermediates for performing lipogenesis, which is the process for creating the substrate to make a lipid droplet. And that process of lipogenesis is reflected by the that the sort of empty, clear material that you see on things like histology. I. And, you know, adipose tissue has this, really, you know, unique specialized function for making glucose into lipid. In that way, not all tissues in the body are are made up to perform dysfunction. And in fact, skeletal muscle and adipose tissue are the really the only places that are responsive to insulin in a way that clears glucose from circulation. And when there are no other there are really no other tissues besides adipose tissue that can perform lipogenesis in ways that are non toxic for the cell. Most other cell types don't perform lipogenesis in great degrees because it requires a lot of ATP

Nick Jikomes 25:59

and sort of, so this process of lipogenesis, what? What form are the fats in when they're stored in these fat cells? Are they triglycerides? Are they? Is it just sort of like a bubble of triglycerides? Is it something else?

Sean Hartig 26:15

It's a it's a triglyceride. And when you're fasting and you need energy to be liberated, lipolysis is the process that liberates that fatty acid from triglyceride, and as a process of of breaking down that droplet, you liberate free fatty acids and glycerol from the triglyceride.

Nick Jikomes 26:47

And like under normal conditions, when I say normal conditions, I mean a metabolically healthy person with some amount of fat, you know, not too much, not too little. How? So I would imagine that the FAT system, the white adipose tissue system, you know, a big part of which, a big part of its purpose, is for fat storage. It's for conserving energy for later, you know, use in an ecological sense, right? Animals constantly, you know, they have to face seasonal changes in food supply. They have to be able to survive for some amount of time without ingesting food. You know, in a time of famine, stay so it makes sense that you have this sort of storage mechanism there. And I wonder how it ties into things like hunger and satiety systems. Is there? Is there signaling that comes directly from fat cells that helps tune how hungry or satiated an animal feels based on its energy storage levels.

Sean Hartig 27:45

Yeah. I mean, this is the cool thing about what adipose tissue does, is it's the it's the sensor for how much energy the body is has on hand, and one of the major endocrine hormones that's made from adipose tissue to reflect that body's sort of energy state is this hormone called leptin. And Leptin is a hormone that has was discovered in the early 90s by Jeff Friedman at Rockefeller, and the discovery of leptin really placed adipose tissue on the map as this vital endocrine tissue. For a long time, adipose tissue was just thought to be this sort of inert sink for storing lipid, but the discovery of hormones like leptin from adipose tissue, place it in this completely separate context of function. And Leptin is a hormone that's detected by the brain and reflects hunger. So your brain is detecting falling levels of leptin from adipose tissue, reduced levels of leptin from adipose tissue, and that tells you when it's when it's time to eat. In obesity, adipose tissue is making too much, too much leptin, and the brain doesn't sense that hunger signal as well anymore.

Nick Jikomes 29:24

So, so are you talking about leptin resistance here?

Sean Hartig 29:26

Yes,

Nick Jikomes 29:27

I see. So despite the fact that there's a lot of adequate tissue making a lot of leptin, in theory, you know, the brain would be detecting those very high levels of leptin. But I guess if you have too much for too long, this, the something breaks, and the brain can no longer respond to that satiety signal, yes,

Sean Hartig 29:44

yes, the sort of delta that the brain senses does not work anymore. And this could. Concept of leptin resistance was part of the reason why leptin therapies for obesity failed in clinical trials.

Nick Jikomes 30:12

I think the idea would be, you could just give someone a bunch of leptin, and that should make them satiated and through the obesity because,

Sean Hartig 30:18

I mean, the really cool, there was, like, a lot of really cool biology associated with these studies that I think were like really, truly pioneering papers. So there was a genetic mouse strain that was, that was, it's called the OB strain. And the obob mice have a congenital leptin knockout, and this gene was mapped to leptin. And Jeff Friedman's lab showed that, you know, adding back leptin to these mice could cause them to lose, to lose weight.

Nick Jikomes 31:03

So they have leptin receptor, but they had no Leptin hormone. That's right, super obese,

Sean Hartig 31:08

yes. So they never, they never feel they get hyper. They're hyperphagic

Nick Jikomes 31:16

eating all the time, basically, yes. So they

Sean Hartig 31:19

just get obese and they'll get polyurea. There's a number of other phenotypes that are associated with OB OB that are also interesting, like they're they're subfertile, or maybe they're even infertile, I think, in in, at least in female mice. And so the key thing discovering that, one of the key discoveries in those studies was that giving mice, those giving mice leptin back, caused them to lose weight. So that was part of the biology that set the stage for companies to generate leptin therapies, right? And unfortunately in people with obesity, they didn't work, because you already have enough leptin there systemically that adding a little bit more therapeutically or pharmacologically was unable to to to break the leptin resistance state. And

Nick Jikomes 32:30

I would imagine, you know, obviously, these mice were engineered on purpose by human beings in a lab. No, no,

Sean Hartig 32:36

these were, these were mice that were that I believe these mice were bred out over a long period of time. Oh, I see it was a mutation that emerged spontaneously at Jackson labs. Oh, wow, in like, the 30s,

Nick Jikomes 32:52

they just noticed that there were these morbidly obese mice, and then they figured out what the mutation was that spontaneously arose, because

Sean Hartig 32:58

in those days that this was before you know, gene sequencing, right? Actually looking, people were actually discovering genes, right? Yeah, yeah. And so it was a really fundamental discovery. And that being said, I mean, there is, like, there is a really cool and exciting leaf, this idea and stories that I really love. So there's a story from Sadaf Farooqi, who's a amazing investigator in in the United Kingdom, and she identified a consanguineous leptin mutation in a Pakistani family. And these children became massively obese. We're talking about a very rare syndrome, maybe less than 30 in the world. And these children, because the leptin deficiency, had hyperphagia and gained weight. However, these individual, these children, responded wonderfully to recombinant leptin therapies.

Nick Jikomes 34:07

I see, presumably, it was a similar genetic mutation to the mice. I

Sean Hartig 34:13

don't know if it's a I don't know what the the sequence similarity between the mutations, but the outcome

Nick Jikomes 34:18

is the same leptin deficiency, right? And

Sean Hartig 34:22

so those giving those in those children, leptin pharmacologically normalized body weight. And those were the that was the leaf for all of the sort of shortfalls of the leptin therapies and wild type, you know, walking around obese people,

Nick Jikomes 34:41

yeah, and I would imagine, you know, but you know, when some of these things were discovered, it was sufficiently long ago that obesity was sufficiently rare that maybe, maybe people were thinking, Oh, this is, this is the genetic basis of obesity, and we're going to cure it this way, right? Of course, you fast forward a few decades, and, you know, huge, huge proportions of the population have. Become obese, which basically implies it can't be a rare mutation like that.

Sean Hartig 35:04

Yes, but there are some mutations that are out there that appear to be associated on call in people. I think that's still up for debate, but there are not. There are rare mutations in some genes that are appear to be causal for obesity, but I think nothing like that's recapitulate in something like it in brain inbred mouse strain.

Nick Jikomes 35:35

So, you know, this is interesting. This brings us to a broader question that I think you're well suited for. So on the one hand, there are clear genetic mutations that can be linked to obesity, like the leptin deficiency phenotype. Of course, these are very rare, and despite those, obesity prevalence has ballooned so quickly over such a wide swath of the human population that it can't be explained away by, you know, a single gene like that. And you know, in the realm of outside the scientific realm, there's a lot of people of variable and arguably dubious expertise who will argue about the extent to which obesity is genetic. How would you start to actually think about that question and explain it to a layperson, the extent to which obesity is genetic versus environmental?

Sean Hartig 36:26

Well, obesity is the classic gene times environment problem. And I want to be really precise in language when I talk about this, because I don't want to be misinformed the population. I don't I don't think it's very clear why obesity rates have skyrocketed in the past 30 years. There are many reasons why people think this has happened. Number one is calorie dense foods being readily available to us. You know, everywhere, right? This is not just readily available high calorie dense foods, but also things like high fructose corn syrup, which has changed, you know, the sweetener which has changed, sugar sweetening of of of beverages and drinks. So that's one thing that people really point to as as a primary causal um, uh, as causation for more obesity in the population. The other one is, people exercise less. People are not as active anymore. I don't know if that's Is that true? I mean, I think that there's populations in the country which don't who, who may not be as active?

Nick Jikomes 38:08

Yeah, my interpretation of the data, you know, depending on where you look, so people say, you know, it's been flat, it's actually or it's actually increased somewhat. And there's some indirect measures of that, I would say, yes, no, maybe. So my interpretation of the data is there's probably been maybe a bifurcation of the population where one subset is exercising more and perhaps some other subset is exercising less, and the net effect, you know, balances out, but it's probably not a uniform effect across the population.

Sean Hartig 38:36

I agree, I agree, and then I think I you

Unknown Speaker 38:42

know,

Sean Hartig 38:46

so the food in an environment that the food in environmental influences are certainly, I think you know, the best causal reason for why people are more obese now than they were 40 years ago. I also think that there's perhaps maybe genetic contributions that are present that have yet to be defined. There are ongoing efforts, I think, to do large scale sequencing to find causal variants. I mentioned Sadaf Farooqi. She's really one of the leaders in this field of identifying variants that are predictive of not just well predictive and causal obesity, not just body weight, but also behaviors associated with obesity. But I don't think it's really, you know, totally clear why there are more people who are obese now than there was. I mean, people are always pointing to towards, you know, a highly available calorie dense foods. And that's certainly explanatory. But, you know, this is an ongoing question that's out there. I mean things like, people think that polluting, you know, more pollution in the, you know, in the in the in the environment, is also a contributing factor, chemicals that are in bottles and stuff like that. Well,

Nick Jikomes 40:23

I want to come back to something you mentioned earlier. You said, you said something like, you know, fat cells are sort of uniquely responsive to anabolic signals like insulin. Obviously, there's an insulin receptor that cells can express to detect and respond to insulin when we think so, a question that I have about insulin resistance, a genuine question that I don't understand yet is, you know, I'll let you explain for everyone what insulin resistance actually is, especially with respect to an adipose tissue, and what that means. But when we say that cells have become insulin resistant, the name of the phenomenon suggests that the cell is no longer responding to insulin. Is that the case, or is the response different than it used to be like? What exactly is insulin resistance in terms of the response to insulin at the cellular level?

Sean Hartig 41:15

So insulin resistance as a feature, really means that a cell requires more of that signal to initiate the pathways that are downstream of the receptor to perform processes like lipogenesis, okay, uptake, and You know, that's a shared feature of other resistance syndromes, right? So leptin resistance, for example, is a similar type of idea. You need more leptin present to activate the leptin receptor in POM C neurons or in the hypothalamus. It's the same concept in the skeletal muscle and the

Nick Jikomes 42:04

adipose tissue. Do you know where the resistance comes from? In the sense of so for insulin resistance, say, is it? Is it can? Can it be explained by cells expressing less insulin receptor than they should, or that something inside the cell is broken so that you need more receptor activation. Do we understand it at that level? One

Sean Hartig 42:24

of the one of the possible explanations for this, which is also very hotly debated, is that adipose tissue is not just adipocytes. In obesity, you have greater numbers of immune cells that get into adipose tissue. Those immune cells produce cytokines that can interrupt the the sensitivity of things like the insulin receptor to insulin, right? So like classic cytokines that are macrophage derived, like TNF alpha and interferon gamma, in low levels, chronically secreted in adipose tissue, can alter insulin regulation of its receptor and the signaling kinase signaling and kinase cascades that are downstream, and that's one of the thoughts behind how sort of insulin signaling gets disrupted and adipose tissue and obesity is because you get infiltration of cells that are not adipocytes, they produce low levels of immune cytokines that have Chronic and prolonged effects on the signaling networks that are important for internalizing glucose into the cell, and that can have, you know, varying effects on like insulin receptor expression, right? But at a base level, those those cytokines interfere with the sensitivity of those signaling networks to the hormones.

Nick Jikomes 44:11

Got it so, so fundamentally. So if we're talking about adipose tissue, insulin resistance means you know at baseline, you know at a certain level of insulin, you had a certain amount of lipogenesis, a certain amount of glucose uptake, and at time point two, after some resistance has developed, you now need some more insulin than you needed before to get the same amount of all that stuff happening.

Sean Hartig 44:35

That's right, exactly right. And are fat cells?

Nick Jikomes 44:39

Are they more prone to insulin resistance, less prone to listen insulin resistance than other cells. Are they? Are they average? Is there something special about them in terms of developing insulin resistance?

Sean Hartig 44:52

That's a really good question. I would say they are more prone to insulin resistance because they are. Highly insulin sensitive in the process that they perform. They're vital for performing glucose uptake. The skeletal muscle is another place where insulin resistance gets manifested, because those are the tissues that are important for performing glucose internalization into cells. The the liver is also a place where where insulin resistance can be can develop, because in people with obesity and diabetes, they they also develop an inability to turn off hepatic glucose production from the liver, and insulin is really important for that physiologic process as well.

Nick Jikomes 45:48

When I want to talk about the the development of both obesity and insulin resistance, I'll let you kind of take it, take it where you want. But, but the question I have to anchor us here is, obviously, calories are an important factor. Here, the amount of calories that you're consuming is an important factor. But another factor that people like to talk about and point to is that, well, it's not just about calories, per se, it's about the particular type of calories one is consuming, and that's going to that's going to be an important factor in terms of your propensity to develop insulin resistance and obesity. Can you talk a little bit about macronutrients, especially dietary fats and dietary carbohydrates, and whether one of them is a bigger driver insulin resistance and fat cells, if one of them is a bigger driver in obesity, and maybe how you start to think about those things? I

Sean Hartig 46:43

i So I think that nutrition is a field where there's a lot of just bad information.

And I think it's certainly true that fructose, for example, is a sugar that is associated with insulin resistance. That effect is primarily from the liver,

in terms of what the adipose tissue sees. It's not a great fructose disposal location, and you can have if lipids like palmitate, floating around that are certainly bad for the metabolic functions of adipocytes, but we really I, in my group, we tend to not think too much about macro nutrients and other sort of nutritional species and how they influence adipose tissue functions, partly because there's, there's no win it's not really a winning path there, right? Because I think there's a lot of information that may or may not be true and can never be true, can ever be proven. I mean, so we my lab, we tend to kind of stay away from those areas for those reasons, because we're really fundamentally interested in what are the precise types of pathways that are that are operant in the fat cell, that are important for performing lipogenesis and regulating obesity phenotypes. So I don't want to dodge the question, but we stay away from that, because I just think, in my opinion, only, that that particular field in nutrition and macronutrient compositions, there's just a lot of debate, and I don't think there's great resolution on what's true and not true

Nick Jikomes 49:21

so and so. So, you know, just getting back to some of the basic physiology of adipose tissue, white adipose tissue in particular. Can you? Can you give us a sense for so, you know, let's say you're a normal, metabolically healthy person, and let's compare that to someone with obesity or metabolic syndrome, where the fat cells are now misbehaving in some way is, you know, what starts to break in the fat cells that would say, I don't know, cause them to accumulate too much fat too quickly, or something like this, or conversely, not be able to get rid of that fat or utilize it for energy purposes. Uh, in what ways did the adipose tissue cells actually start to lose their original function in a metabolically unhealthy state?

Sean Hartig 50:10

So this, this is a part of the response to the micro environment. Is one important way that adipose tissue loses its ability to to perform its metabolic and endocrine functions. So in adipose tissue, during the early parts of obesity, the adipocyte in that tissue requires expansion of the endothelial cell network, and this is important for providing nutrients and regulating the oxygen content in the tissue, so that adipose tissue has the signals that cause expansion. Okay, and at some point that chronic stress of obesity begins to outstrip a lot of the endothelial cell network, and so things like hypoxia start to set in other strong inflammatory responses from

Nick Jikomes 51:24

do you mean literally, like, the endothelial tissue can't expand enough to accommodate the mass that's forming, and, like, you know, NOx oxygen can't quite diffuse into all the little crevices and things like that. Yes,

Sean Hartig 51:38

that's precisely correct, I see, so you're stripping the tissue of critical nutrients, I see, and that everything's packed in too tight. Basically, that's right. And that appears to be really what the tipping part of the tipping point that occurs in adipose tissue is that the endothelial network doesn't the endothelial network just gets outstripped by calorie demand, and that's associated with accumulation of things like macrophages and T cells. And that event where you get accumulation of non adipocyte cells, and the tissue appears to interfere with the ability of the adipocyte to store more energy properly. And there have been a lot of cool studies in mice and some correlative perspective analyzes in people, where, if they perform genetic manipulations of, you know, endothelial cell interacting molecules, you can make huge adipose tissues, and you can cause mice to get, like, 100 grams, right?

Nick Jikomes 52:50

And no mouse would be, what, 20 grams maybe.

Sean Hartig 52:54

So if you put a mouse on a high put a put a standard black six strain mouse on a high fat diet for, let's say, 12 weeks, a high fat diet being 60% of its diet coming from fat that mouse will weigh, you know, between 40 and 50 grams. That's

Nick Jikomes 53:12

a big mouse, right? These mice

Sean Hartig 53:14

that are genetically engineered to expand adipose tissue mass and maintain all of the endothelial structures appropriately, they can be up to 100 grams, and they look like hockey pucks, right? And histologically, they have these really small subcutaneous fat cells

Nick Jikomes 53:38

I see, so you've sort of maximized the amount of subcutaneous fat storage they're capable of packing on.

Sean Hartig 53:44

I mean, I don't know maximizing. I mean, you just really make them like super capable of of making and storing fat very well. And so I really love genetic studies like that, because it really strongly implicates that if you can maintain this, like healthy micro environment of adipose tissue, you can make it expand in ways that don't, don't really make the animal diabetic,

Nick Jikomes 54:20

I see so these animals get ultra fat, but it's subcutaneous fat. The endothelial tissue is expanding to accommodate that fat, and so you're not getting the same levels of insulin resistance and inflammation and things like that. That's

Sean Hartig 54:35

right, that's right. And so that really implicates these like interacting cells in the microenvironment is really important for talking to the adipocyte in ways that allows the adipocyte to get the adipose tissue to be better at storing energy. It doesn't mean that it's still not bad to be overweight. It's still bad to be overweight. It's not good for your skeleton. For example. Yeah, but it does say that making adipose tissue healthy can protect the organism from

Nick Jikomes 55:09

Yeah, I mean, and like you said, it does. It does show us that it really has something to do with, you know, how the tissues expanding and being packed together, and even though human beings don't put on weight like, like the hockey puck mouse model, the fact that we don't put on weight that way tells us, you know that, that you know tells us what, what part of the problem is. So I have a question. So, so when people become obese and these things start to happen, the fat cells, everything's just getting packed in too much, you start to get some hypoxia that the cells can't properly be, you know, given nutrition and things like this, just because of, because of that density, because everything's packed in like that, a lot of that's going to have to do with, I think, the visceral fat that we know people put on that we were talking about before. I guess one little question I have here is, maybe, when we think about things like inflammation, chronic inflammation, and all of these extra non adipose cells coming into the mix and making every you know, making things packed in so tight, to what extent are those immune cells that inflammation. To what extent is that sort of a cause versus a consequence? Here? Is there something, you know, is something breaking that's then creating a signal that the immune system is listening to, where the immune system is trying to come in and fix it? Or is the immune system somehow getting in there for whatever reason, and then, you know, that's sort of a upstream in the process of obesity. That's

Sean Hartig 56:45

a super spot on question, right? And it's something that we're in the field, we're thinking a lot about, and there were a lot of really pioneering in nice stories in the 20 years ago or so, which which found higher levels of inflammatory cytokines and mouse models and in people, it was thought that these were accumulation of these cytokines, like TNF and interferons and stuff like that, that those are really causal for diabetes. Accumulation of those cytokines in adipose tissue really causal for diabetes. And so there were a lot of clinical trials for, you know, drugs that temper, TNF alpha, for example, those, those trials really showed no benefit or insulin resistance, no obesity, no no reduction in body weight, despite all of the stuff that that had been shown in rodents, which was like everywhere. And so it's also true that anti diabetic therapies like metformin and thiazoldine diones and GLP one receptor agonists, the effect associated with those drugs coincides with reduction of inflammation and adipose tissue. So uh. However, the idea that like that these drugs, anti inflammatory drugs exert really no benefit on body weight or glucose metabolism in people, would really suggest that inflammation in inflammatory cell responses in adipose tissue is really a response, a reparative response, in some way that we don't fully understand well, that you need sort of macrophages to get in there and help remodel The adipose tissue in ways that are beneficial for, you know, making the tissue size larger, right? And that's what we think, too. And in our group, we think that those, those responses at the level of inflammation are important for for like reparative responses, you perform better so.

Nick Jikomes 59:22

But you know, supposing that's true, they're going in there to repair something, um, they might get, for whatever reason, caught up and then become part of the problem as kind of a side effect of trying to come in and fix something. But again, supposing that's true, my guess is we don't yet know what that signal, what they're detecting, and what maybe they're going in to try and fix I don't

Sean Hartig 59:42

think we know what that signal is very well, at least precisely. We don't know what it is precisely.

And this is not to diminish the idea that whole body inflammation in obesity and diabetes isn't bad. I think it's there's certainly room to implicate inflammation as being bad. I just don't know that we know the mechanism as to why it's bad or why it's not bad. And that's a that's a question of intense debate that think we'd all like to know the answer to implementing adipose tissue bad or good, or is it just a biomarker? So for my group, we think it's more just a biomarker of adipose tissue dysfunction.

Nick Jikomes 1:00:38

Are fat cells, you know, given their energy storage functions, given what they do, do they harbor sort of bigger or more mitochondria? Are they producing more reactive oxygen species? Are they somehow more prone to oxidative stress, or anything like that?

Sean Hartig 1:00:56

So there's certainly a lot of evidence to suggest that bigger fat cells in obesity have compromised mitochondrial function. White fat cells that you would see in the visceral space, even in the subcutaneous adipose tissue depots, they have far less mitochondria than a beige adipocyte, far less mitochondria than a brown fat cell, and the mitochondrial function is actually like is really important for performing the metabolic reactions in the cell that allow lipogenesis to be performed appropriately. So as far as like reactive oxygen species and oxidative stress, those terms, I think, have become more confusing over the years, because at some level, you need reactive oxygen species to be generated in quantities that serve signaling purposes in the cell. In fact, like for mitochondria to function normally, you generate reactive oxygen species as a byproduct. Yeah.

Nick Jikomes 1:02:18

So what you're saying basically is reactive oxygen species aren't all bad all the time. Cells are, in some sense, generating them on purpose. And it's, you know, it's actually serving a useful signal and function. Yes,

Sean Hartig 1:02:29

yes, yes. So knowing where that again, that tipping point would be to make them really, you know, pathological is something different altogether. But I want to say that not all Ross and oxidative signals in the fat cell are all bad. Think that there's like location that matters, the concentration that matters, the density of those stresses in the inside the cell, compartmentalization of those signals that may cause them to be bad or good, and I think that those types of terms get get sort of thrown around a lot as being causal, but that there's no doubt that reactive oxygen species from the mitochondria occurs right in the cell as part of its normal operation of the electron transport chain, and certainly also true that alterations in the generation of ROS could be could be bad For the cell. That could mean like less reactive oxygen, reactive oxygen species generated that could also be bad, right in the liver. It appears that in obesity and diabetes, you have a slowing of the electron transport chain liver, and that's essentially associated

Unknown Speaker 1:03:57

with with

Sean Hartig 1:04:01

like worsening tempering of the Ross that's generated from that, from those activities,

Nick Jikomes 1:04:11

yeah, the record of oxygen species are generated as a natural consequence of various physiological activities and cells, and that is used as a signal for normal, healthy, self functioning. You know, you could imagine things going in either direction, too too much or too little. Reactive oxygen species could be problematic, right, right?

Sean Hartig 1:04:29

But this idea that there's like, broad based, you know, negative consequences of reactive oxygen species, I think, is just not correct. And I think that's pretty well agreed upon people in our field.

Nick Jikomes 1:04:47

I want to ask you about the liver a little bit and fatty liver disease. So obviously, you know white adipose tissue, when you think about energy storage, you know that's tissue where you know fat is supposed to accumulate. The impression. One gets is that fatty liver disease represents an accumulation of fat in the liver, and you're not really supposed to accumulate much fat in the liver. Can you just give us? Let's just start very basic with what is fatty liver disease, and to what extent is the liver supposed to be accumulating any fat.

Sean Hartig 1:05:15

So the in the liver is we do have a little bit of work in the liver, but it's not my major space of expertise, so I'll tell you what I know. An